The present invention relates to a novel compound, its method of making, its method of use and intermediates thereof. It is a pharmaceutically active compound useful as an antagonist of serotonin at the 5HT2A receptor. It is useful in treating conditions and diseases such as schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud""s phenomenon, intermittent claudication, coronary or peripheral vasospasms, fibromyalgia, cardiac arrhythmias, thrombotic illness, controlling the extrapyramidal symptoms associated with neuroleptic therapy, depressive and bipolar disorders, obsessive-compulsive disorders, insomnia and sleep apnea.
(+)-xcex1-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol has the following structure: 
It is a novel pharmaceutically active compound in the treatment of conditions and diseases useful as an antagonist of serotonin at the 5HT2A receptor, and as such; is useful in a variety of treatments such as schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud""s phenomenon, intermittent claudication, coronary or peripheral vasospasms, fibromyalgia, cardiac arrhythmias, thrombotic illness, controlling the extrapyramidal symptoms associated with neuroleptic therapy, depression, bipolar disorders, obsessive-compulsive disorders, insomnia and sleep apnea. xcex1-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol has been generically described in U.S. Pat. No. 5,169,096, issued Dec. 8, 1992, the disclosure of which is incorporated herein by reference. (+)-xcex1-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol was thereafter described in U.S. Pat. No. 5,134,149, issued Jul. 28, 1992, the disclosure of which is incorporated herein by reference. U.S. Pat. No. 5,700,813, issued Dec. 23, 1997, U.S. Pat. No. 5,700,812, issued Dec. 23, 1997, U.S. Pat. No. 5,561,144, issued Oct. 1, 1996, U.S. Pat. No. 5,721,249 issued Feb. 23, 1998 and U.S. Pat. No. 5,874,445 issued Feb. 23, 1999, the disclosure of each which is incorporated herein by reference, describe the use of (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as 5HT2A receptor antagonists in the treatment of a number of disease states as described above. Other U.S. Patents, which describe the use of the generic species in the treatment of a number of disease states, are U.S. Pat. Nos. 4,783,471; 4,877,798; 4,908,369; 4,912,117; 5,021,428; 5,106,855; 5,618,824 and U.S. Pat. No. 5,478,846, which generically discloses intermediates. Each of the preceding disclosures is incorporated herein by reference.
The compound of the present invention has been found to be an active metabolite of (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol by virtue of its ability to act as an antagonist at the 5HT2A receptor, and represents the major metabolite of (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol found in plasma. The unsulfated version of the present invention (+)-xcex1-(3-hydroxy-2-methoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidinemethanol is also a metabolite of (+)-xcex1(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as described in Heath, T. G. et al. J. Am. Soc. Mass Spectrum. (1997), 8(4), 371-379, and Scott, D. et al. J. Pharm. Biomed. Anal. (1998), 17(1), 17, incorporated herein by reference. Even though the present invention is a mono sulfated conjugate of (+)-xcex1-(3-hydroxy-2-methoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidinemethanol, unexpectedly, according to tests described hereafter, it has been found to cross the blood-brain barrier and therefore may be useful in the treatment of central nervous system conditions or diseases which are treated by antagonizing the effects of serotonin at the 5HT2A receptor.
It is an object of the present invention to provide a compound useful in treating a variety of diseases or conditions. This compound should have a binding profile (affinity or lack of affinity for specific receptors), which permits therapeutic activity without undue side effects. For example, too much affinity for the alphal receptor may result in orthostatic hypotension and sedation. Too much affinity for the dopamine 2 (D2) receptor can result in hyperprolactinemia, extrapyramidal side effects (EPS) and tardive dyskinesia. Also, preferably the present invention should cross the blood-brain barrier in order to be active against diseases or conditions that affect the central nervous system. The present invention solves these problems by having an effective binding profile sufficient to treat certain diseases or conditions without significant side effects and treats certain central nervous systems diseases or conditions.
The present invention is a compound of Formula I, II or III 
or a pharmaceutically acceptable salt thereof, and methods for the preparation of said compounds.
The present invention also comprises a pharmaceutical composition comprising the compounds of formula I, II or III and a pharmaceutically acceptable carrier; a method of treating a patient for diseases of schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud""s phenomenon, intermittent claudication, coronary or peripheral vasospasms, fibromyalgia, cardiac arrhythmias, thrombotic illness and in controlling the extrapyramidal symptoms associated with neuroleptic therapy, depressive and bipolar disorders, obsessive-compulsive disorders, insomnia and sleep apnea, by administering a compound of formula I, II or III. Further, the present invention also comprises an intermediate, and methods of making the unsulfated versions of the forgoing compounds. The present invention also comprises collecting (isolating) the compounds of interest from a sample collected from a patient.
In general, various terms as used herein shall have the following meanings unless otherwise defined:
(1) xe2x80x9cPharmaceutically acceptable saltxe2x80x9d means either an acid addition salt or a basic addition salt, which is compatible with treatment of patients for the intended use.
xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d is a non-toxic organic acid addition salt of the base compounds represented by Formula I, II or III or any of its intermediates. Some examples of inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids, which form suitable salts, include the mono-, di, and tricarboxylic acids. Examples of such acids are acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, and sulfonic acids such as p-toluenesulfonic acid, methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition hydrophilic organic salts in comparison to their free base forms generally demonstrate higher melting points.
xe2x80x9cPharmaceutically acceptable base addition saltsxe2x80x9d means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of its intermediates. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium or organic amines such as methylamine, trimethylamine and picoline.
(2) xe2x80x9cPatientxe2x80x9d means a warm blooded animal, such as, for example, rat, mouse, dog, cat, guinea pig, and primates such as a human.
(3) xe2x80x9cTreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d means to prevent or alleviate symptoms, eliminate the causation of the symptoms either on a temporary basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
(4) xe2x80x9cTherapeutically sufficient amountxe2x80x9d means a quantity of the compound that is effective in treating the named disorder or condition.
(5) xe2x80x9cAmount sufficient to antagonize the effects of serotonin at the 5HT2A receptorxe2x80x9d means a quantity of the compound that is effective in antagonizing the effects of serotonin at the 5HT2A receptor.
(6) xe2x80x9cAdministering or administrationxe2x80x9d means a suitable route for giving a therapeutically sufficient amount of drug to a patient. Examples of suitable routes are oral, buccal, sublingual, parenteral, intravenous and topical, including a topical patch administration. Furthermore, this also means giving a prodrug to the patient in order to produce the compound of interest at the site of action in the body. For example, the prodrug (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol is administered to the patient to provide at least the compound sulfuric acid mono-(+)-[3-({1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-hydroxy-methyl)-2-methoxy-phenyl]ester and possibly the (xe2x88x92) enantiomer thereof.
(7) xe2x80x9cSchizophreniaxe2x80x9d means a condition where a patient suffers a mental disturbance that lasts at least 6 months and includes 1 month of active-phase symptoms, such as two or more of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.
(8) xe2x80x9cAnxietyxe2x80x9d means a condition where a patient suffers an apprehension of danger and dread accompanied by restlessness, tension, tachycardia and dyspnea unattached to a clearly identifiable stimulus.
(9) xe2x80x9cVariant anginaxe2x80x9d means a condition where the patient suffers from coronary vasospasms, which produce the chest pains associated with angina. These vasospasms typically occur while the patient is at rest.
(10) xe2x80x9cAnorexia nervosaxe2x80x9d means a condition where a patient refuses to maintain a minimally normal body weight and is intensely afraid of gaining weight, and exhibits a significant disturbance in the perception of the shape or size of his or her body.
(11) xe2x80x9cRaynaud""s phenomenonxe2x80x9d means a condition where the patient suffers from a spasm of the digital arteries, with blanching and numbness of or pain of the fingers, often precipitated by cold.
(12) xe2x80x9cIntermittent claudicationxe2x80x9d means a condition where the patient suffers from, due to ischemia of the muscles, attacks of lameness and pain, brought on by walking, chiefly in the calf muscles; however, the condition may occur in other muscle groups.
(13) xe2x80x9cCoronary or peripheral vasospasmsxe2x80x9d means a condition where the patient suffers from contraction and hypertonia of the muscular coats of the cardiac or peripheral blood vessels.
(14) xe2x80x9cFibromyalgiaxe2x80x9d means a condition where the patient suffers chronically from numerous symptoms such as, for example, widespread generalized musculoskeletal pains, aching, fatigue, morning stiffness and a sleep disturbance which can be characterized as an inadequacy of stage 4 sleep.
(15) xe2x80x9cCardiac arrhythmiaxe2x80x9d means a condition where the patient suffers from any variation from the normal rhythm of the heart beat.
(16) xe2x80x9cThrombotic illnessxe2x80x9d means a condition where the patient suffers from a clotting within a blood vessel, which may cause infarction of tissues supplied by the vessel.
(17) xe2x80x9cExtrapyramidal symptomsxe2x80x9d means a condition where the patient suffers from side effects from the administration of neuroleptic agents such as haloperidol and chloropromazine. These extrapyramidal side effects (EPS) can encompass Parkinsonian-like syndromes, akathasia and acute dysitonic reactions.
(18) xe2x80x9cDepressionxe2x80x9d means a condition where the patient suffers from a temporary mental state or chronic mental disorder characterized by feelings of sadness, loneliness, despair, low self-esteem and self-reproach; accompanying signs include psychomotor retardation or less frequently agitation, withdrawal from social contact and vegetative states such as loss of appetite and insomnia.
(19) xe2x80x9cBipolar disorderxe2x80x9d means a condition where the patient suffers from alternating periods of euphoria and depression.
(20) xe2x80x9cObsessive-compulsive disordersxe2x80x9d or xe2x80x9cOCDxe2x80x9d means a condition where the patient exhibits recurrent obsessions or compulsions that are severe enough to be time consuming (i.e., take more than an hour a day) or cause marked distress or significant impairment. Obsessions are persistent ideas, thoughts, impulses, or images that are experienced as intrusive and inappropriate and that cause marked anxiety or distress. Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) the goal of which is to prevent or reduce anxiety or distress, not to provide pleasure or gratification.
(21) xe2x80x9cInsomniaxe2x80x9d means a condition where the patient suffers from an inability to sleep in the absence of external impediments, during the period when sleep should normally occur.
(22) xe2x80x9cSleep apneaxe2x80x9d means a condition where the patient suffers from a stoppage of breathing for at least 10 seconds or more, and usually greater than 20 times/hour, causing measurable blood deoxygenation.
(23) xe2x80x9cPharmaceutically acceptable carrierxe2x80x9d is a non-toxic solvent, dispersant, excipient, adjuvant or other material, which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral administration.
(24) xe2x80x9cEnantiomersxe2x80x9d are a pair of isomers that are mirror images of each other and not superposable.
(25) xe2x80x9cRacematexe2x80x9d means a composite of two enantiomeric species. It is devoid of optical activity.
(26) xe2x80x9cStereoisomerxe2x80x9d is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
(27) xe2x80x9cC1-C4 alkylxe2x80x9d and C1-6 alkylxe2x80x9d means a straight or branched chain hydrocarbon radical of one to four and one to six carbon atoms. Included within the scope of these terms are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, neopentyl, hexyl and the like.
(28) xe2x80x9cAralkylxe2x80x9d means an aryl or diaryl moiety connected to the remainder of the molecule via an alkylene bridge. This alkylene bridge can be straight or branched-chained and is one, two, three, four, five or six carbons in length. xe2x80x9cAryl means an aromatic radical having six atoms in a single ring system such as phenyl or a fused ring system such as 1-napthyl, 2-napthyl and the like. The aryl or diaryl group may be optionally substituted as described herein. The substitutions may be at the ortho, meta or para positions as appropriate. Examples of preferred aralkyls are benzyl, phenylethyl, propylphenyl and diphenylbutyl.
(29) xe2x80x9cOptionally substitutedxe2x80x9d means that the referenced moiety is substituted as defined herein by the same or different substituents, i.e. independently selected, from the group; of hydrogen, halogen (fluorine, chlorine, iodine or bromine), C1-6 alkyl, C1-6 alkoxy, C(xe2x95x90O)H, C(xe2x95x90O)C1-6 alkyl, CF3 or hydroxy with one, two or three substituents as is suitable to the structure.
(30) xe2x80x9cProdrugxe2x80x9d means a compound given to a patient, which is then metabolized in the patient to another active compound. In the present invention the prodrug is (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
(31) xe2x80x9cSamplexe2x80x9d means a quantity of either plasma, urine or other component of the body from which the compounds of the present invention may be found and isolated therefrom.
(32) xe2x80x9cOptically active isomersxe2x80x9d are isomers that rotate the plane of polarized light and are designated (+) or (xe2x88x92).
The compounds of the invention may be prepared by the synthetic routes described below in the Schemes or other methods, which may be apparent to those skilled in the art. The enantiomerically pure compounds of the invention may be prepared as outlined in Scheme A. The scheme illustrates the synthesis of the (+) enantiomer; however, as would be evident to one with ordinary skill in the art, by starting with the appropriate (xe2x88x92) enantiomer the sequence shown in Scheme A would afford the corresponding (xe2x88x92) enantiomer of the invention. 
Step A1: The compound 1, (+)-xcex1-(3-hydroxy-2-methoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, a known metabolite of (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as described in Heath, T. G. et al. J. Am. Soc. Mass Spectrom. (1997), 8(4), 371-379, and Scott, D. et al. J. Pharm. Biomed. Anal. (1998), 17(1), 17-25, (also see Scheme C), is reacted with a suitable acylating agent to provide the diprotected compound 2, wherein Pg is a protecting group such as C1-6 alkylsulfonyl, trifluoroacetyl, or C(xe2x95x90O) C1-6 alkyl other protecting groups may be used as is known to one skilled in the art. The groups may be the same or different groups, but typically are the same. Suitable acylating agents are, for example, anhydrides and acid chlorides or bromides, with anhydrides preferred. The reaction is performed under standard acylating conditions well known to those with ordinary skill in the art.
Step A2: The diprotected compound 2 is then selectively hydrolyzed to the monoprotected phenol 3. The reaction may be carried out in an aqueous protic solvent with an alkali bicarbonate. Examples of aqueous protic solvents are ethanol, methanol, propanol and isopropanol that have been diluted with varying proportions of water. The preferred aqueous protic solvent is aqueous methanol. Examples of alkali bicarbonates are sodium, cesium or potassium bicarbonate, sodium bicarbonate being preferred. The reaction temperature may vary from 0xc2x0 C. to the boiling point of the solvent. The preferred temperature is between 0xc2x0 C. and room temperature.
Step A3: The monoprotected phenol 3 is converted to the intermediate mono sulfuric acid ester 4 by reacting said monoprotected phenol with a suitable sulfating agent. Suitable sulfating agents are those compounds capable of adding sulfate at the desired position. Examples of suitable sulfating agents are sulfur trioxide pyridine complex, sulfur trioxide triethylamine complex, sulfur trioxide dimethylformamide complex, sulfuric acid-dicyclohexylcarbodiimide, chlorosulfonic acid with acid or base, pyridine sulfur trioxide complex being preferred. The reaction is carried out in an appropriate organic solvent. Examples of appropriate organic solvents are benzene, toluene, acetonitrile, dimethylformamide, dichloromethane and chloroform. The preferred solvent is acetonitrile. The reaction temperature may vary from room temperature to the boiling point of the solvent, a temperature of about 45xc2x0 C. is preferred.
Step A4: Preferably without isolation of the sulfuric acid ester 4 is reacted in situ with an alkali metal carbonate such as sodium, potassium, or cesium carbonate, potassium carbonate preferred, in an aqueous protic solvent such as methanol-water to afford the sulfuric acid ester alcohol 5. The reaction temperature may vary from room temperature to boiling point of the solvent, the boiling point of the solvent is preferred.
Scheme B illustrates the synthesis of the racemate of 15 also known as Formula I. 
Step B1: Guiacol, the compound 6, available from the Aldrich Chemical Company, is reacted with a reagent to provide a suitable protecting group, preferably a suitable trialkylsilyl halide to form the monomethoxysilylether derivative 7. Suitable trialkylsilyl halides, are compounds that would react with a phenolic oxygen to produce a compound wherein R1=Si(R4)3 and R4 is C1-6 alkyl for example, t-butyldimethylsilyl chloride and triisopropylsilyl chloride, with triisopropylsilyl chloride being preferred. The purpose of the silyl substituent (R1), besides protecting the phenolic oxygen, is also to inhibit abstraction of the aromatic hydrogen that is adjacent (ortho) to the OR1 substituent, when the compound is treated with a strong base. Consequently, upon reaction of said compound with a strong base, the aromatic hydrogen ortho to the methoxy substituent is abstracted regioselectively. Such a strategy has been previously invoked by B. Trost, et al., Tetrahedron Lett., 1985, 26, 123-126 and J. J. Landi, et al. Synthetic Commun., 1991, 21, 167-171 incorporated herein by reference. The reaction is typically effected by reaction of a trialkylsilyl halide, in the presence of a suitable nucleophilic catalyst such as imidazole or 4-dimethylaminopyridine, imidazole being preferred, in a suitable polar aprotic solvent. Examples of polar aprotic solvents are dimethylformamide, 1-methyl-2-pyrrolidinone, dimethylsulfoxide, hexamethylphosphoramide, acetone and acetonitrile. The preferred solvent is dimethylformamide. The reaction can be run at a temperature from 0xc2x0 C. to ambient temperature, ambient temperature being preferred.
Step: B2: The silyl derivative 7 is then reacted with a C1-4 alkyl lithium, such as n-butyl, sec-butyl or t-butyl lithium, n-butyl lithium being preferred, in an ethereal solvent, such as diethyl ether, tetrahydrofuran or dimethoxyethane, with tetrahydrofuran being the preferred solvent. This results in the regioselective formation of the anion. Addition of a suitable N-protected piperidinyl Weinreb amide derivative 8, produces the ketone 9. Suitable N-protecting groups (R2) are those that would be stable under the reaction conditions, and examples can be found in Protective Groups in Organic Synthesis, 2nd edition, Theodora Greene, et al., John Wiley and Sons, Inc., incorporated herein by reference. The reaction temperature may be varied between xe2x88x9278xc2x0 C. to the boiling point of the solvent.
Step B3: The ketone 9 is N-deprotected to produce the aroyl piperidine10. Reagents and conditions to effect the deprotection would depend upon the nature of the N-substituent and would be apparent to one with ordinary skill in the art.
Step B4: Reaction of aroyl piperidine 10 with a suitable alkylating agent 11 forms the alkylated piperidine 12. A suitable alkylating agent is where X=a suitable leaving group. A xe2x80x9csuitable leaving groupxe2x80x9d is a moiety that is displaced or removed for the reaction to take place. Examples of suitable leaving groups are halogens, benzenesulfonate, methanesulfonate or p-toluenesulfonate, with methanesulfonate being preferred. The reaction is performed in the presence of a suitable organic base, in a polar aprotic solvent. Examples of suitable organic bases are pyridine, triethylamine, lutidine and N-ethyldiisopropylamine, with N-ethyldiisopropylamine preferred. Examples of suitable polar aprotic solvents are acetone, acetonitrile, dimethylformamide, 1-methyl-2-pyrrolidinone, dimethylsulfoxide and hexamethylphosphoramide. The preferred solvent is acetonitrile. The reaction may be conducted at room temperature to the boiling point of the solvent. The preferred temperature being the boiling point of the solvent.
Step B5: The alkylated piperidine 12 is converted to the hydroxy ketone 13 by treatment with a suitable desilylating agent in an ethereal solvent. A suitable desilylating agent is a compound, which removes the silyl protecting group. Examples of suitable desilylating agents are ammonium tetrafluoride, tetra-N-butylammonium fluoride and pyridine hydrofluoride, tetra-N-butylammonium fluoride being preferred. Suitable ethereal solvents are diethyl ether, tetrahydrofuran or dimethoxyethane, tetrahydrofuran being preferred. The reaction temperature may vary from 0xc2x0 C. to the boiling point of the solvent, with ambient temperature being preferred.
Step B6: Hydroxy ketone 13 is converted to the intermediate sulfuric acid ester 14 by reacting said hydroxyketone with a suitable sulfating agent. Suitable sulfating agents are those compounds capable of adding sulfate at the desired position. Examples are sulfur trioxide pyridine complex, sulfur trioxide triethylamine complex, sulfur trioxide dimethylformamide complex, sulfuric acid-dicyclohexylcarbodiimide and chlorosulfonic acid with acid or base. The reagent sulfur trioxide pyridine complex being preferred. The reaction is carried out in an appropriate organic solvent for the reaction to occur. Examples of appropriate organic solvents are benzene, toluene, acetonitrile, dimethylformamide, dichloromethane and chloroform. The preferred solvent is acetonitrile. The reaction temperature may vary from room temperature to boiling point of the solvent. The preferred temperature being the boiling point of the solvent.
Step B7: Preferably without isolation, the sulfuric acid ester ketone14 is reduced to the racemic alcohol ester 15, by an suitable reducing agent. A suitable reducing agent is a compound, which reduces this ketone to the desired alcohol. Examples of suitable reducing agents are alkali metal borohydrides, such as lithium or sodium borohydride with sodium borohydride being the preferred reducing agent. The reaction is performed in an appropriate protic organic solvent such as ethanol, isopropanol, propanol or methanol, ethanol being the preferred solvent. The reaction temperature may vary from 0xc2x0 C. to the boiling point of the solvent, with room temperature being preferred.
B8: Optionally reacting compound 15 or its enantiomers with an inorganic or organic acid capable of forming a pharmaceutically acceptable salt.
In another embodiment of this invention, the method of synthesis of the intermediate alcohol 1 is described in Scheme C. 
Step C1: The benzoyl piperidine 10 from Scheme B is reacted with the acid halide 16 to obtain the ketoamide 17. The substituent X represents a halogen chosen from Br, Cl and F with Cl being the preferred halogen. The substituent R1 represents the group Si(R3)4 and R3 represents C1-4 alkyl. The reaction can be performed under conditions that are well known to one skilled in the art, for instance, in a suitable organic solvent and in the presence of a suitable base. Examples of suitable organic solvents are aromatic hydrocarbons such as benzene, toluene, mesitylene and xylenes; aliphatic hydrocarbons such as pentane, hexane and heptane and aliphatic ethers such as diethyl and diisopropyl ether. The preferred solvent being toluene. Suitable bases would be tertiary organic amines, and aqueous solutions of inorganic bases. Inorganic bases suitable for use in the present invention include alkali hydroxides, alkali carbonates and alkali bicarbonates. Most preferred is an aqueous solution of an alkali hydroxide such as sodium hydroxide.
Step C2: The ketoamide 17 is reduced to produce the piperidine alcohol 18 as a racemate with a suitable reducing agent in an organic solvent. Reducing agents suitable for use in the method are borane complexes, aluminum hydrides, alkali aluminum hydrides, alkali borohydrides particularly in the presence of Lewis or organic acids. The preferred reducing agent is borane-methyl sulfide complex. Organic solvents that can typically be used for the reaction are ether, tetrahydrofuran, dimethoxyethane and toluene, with toluene being preferred. The reaction temperature at which the reaction can be run may vary from xe2x88x9250xc2x0 C. to the boiling point of the solvent. Most preferred is a temperature of about xe2x88x9230xc2x0 C. to room temperature.
In a further embodiment, the piperidine alcohol 18 can be obtained in an enantioenriched state by the addition of a catalytic amount of a chiral oxazaborolidine to Step C2 above. The use of such reagents for the enantioselective reduction of ketones has been illustrated in a review by Walbine S. et al., Tetrahedron Asymmetry, 1992, 3, 1475-1504, incorporated herein by reference. Suitable chiral oxazaborolidines for the reaction are (R) or (S) -3,3-diphenyl-1-substituted pyrrolidino[1,2-c]-1,3,2-oxazaboroles and (R) or (S) -3,3-di-xcex2-naphthyl-1-substituted pyrrolidino[1,2-c]-1,3,2-oxazaboroles. The preferred chiral catalyst being (R) or (S)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole (2-methyl-CBS-oxazaborolidine or methyl oxazaborolidine).
Step C3: Optionally, the piperidine alcohol 18 can be deprotected to produce the racemate of the phenol alcohol 1 by treatment with a suitable desilylating agent in an organic solvent. A suitable desilylating agent is a compound, which removes the silyl protecting group. Examples of suitable desilylating agents are ammonium tetrafluoride, tetra-N-butylammonium fluoride and pyridine hydrofluoride, with ammonium tetrafluoride preferred. Suitable organic solvents for the reaction are protic solvents such as alcohols or ethereal solvents such as dialkylethers. The reaction temperature may vary from ambient temperature to the boiling point of the solvent.
Step C4: The piperidine alcohol 18 as a racemate or in enantioenriched form can then be reacted with a suitable chiral acid to give a mixture of diastereomeric esters 19, wherein R3 is a suitable resolving agent. Suitable resolving agent means a moiety capable of separating enantiomers from a racemate by formation of diastereomeric esters. Some examples of suitable resolving agents are (R) or (S) mandelic acid, acetyl mandelic acid, xcex1-methoxyphenylacetic acid, xcex1-methoxy-xcex1-(trifluoromethyl)-phenylacetic acid, -2-(6-methoxy-2-naphthyl)-propionic acid, xcfx89-camphanic acid, trans-1,2-cyclohexane dicarboxylic acid anhydride and 5-oxo-2-tetrahydrofurancarboxylic acid as described in Stereochemistry of Organic Compounds, Ernest L. Eliel et al., John Wiley and Sons, Inc., incorporated herein by reference. The preferred resolving agent is (R) or (S) xcex1-methoxyphenylacetic acid. The reaction is typically performed in an organic solvent in the presence of a coupling promoter such as dicyclohexylcarbodiimide or carbonyl diimidazole and a nucleophilic catalyst such as imidazole or 4-dimethylamino-pyridine. The preferred coupling promoter is dicyclohexylcarbodiimide, and the preferred nucleophilic catalyst is 4-dimethylaminopyridine. Suitable organic solvents for the reaction are aprotic solvents such as chloroform, methylene chloride, dimethylformamide, acetonitrile and toluene, with methylene chloride being preferred. The reaction may be performed at room temperature to the boiling point of the solvent, the boiling point of the solvent is the preferred temperature. The mixture of diastereomeric esters is then separated by techniques that are well known to one with ordinary skill in the art, to produce the two individual diastereomers of compound 19. Separation of the diastereomers, for example, can be accomplished by crystallization or column chromatography, with the preferred method of separation being chromatography.
Step C5: The pure individual diastereomer of 19 is converted to the phenol ester 20 by treatment with a suitable desilylating agent in a protic solvent. Examples of suitable desilylating agents are ammonium tetrafluoride tetra-N-butylammonium fluoride and pyridine hydrofluoride, with ammonium tetrafluoride preferred. Suitable protic solvents are methanol, ethanol, propanol, butanol and isopropanol, methanol being preferred. The reaction temperature may vary from ambient temperature to the boiling point of the solvent, the boiling point of the solvent being preferred.
Step C6: The phenol ester 20 is hydrolyzed to a single enantiomer of the phenol alcohol 1 by reaction of the ester with a suitable base in a water-protic solvent solution. Suitable bases to effect the reaction are alkali metal hydroxides and carbonates, such as sodium, potassium, lithium and cesium hydroxides and carbonates, with the preferred base for the reaction being potassium carbonate. Suitable water-protic solvent solutions are methanol-water, ethanol-water, propanol-water, isopropanol-water and butanol-water, with methanol-water preferred. The reaction temperature may vary from 0xc2x0 C. to the boiling point of the solvent, with a temperature of about 20-25xc2x0 C. preferred.
Also, as a further embodiment of the invention compound 1 can be isolated as an acid addition salt, whose preparation can be accomplished by methods that are well known to one with ordinary skill in the art.
The compounds of the current invention may be isolated from a sample such as human plasma by taking a sample of said human plasma from a patient that has been administered a therapeutically effective amount of (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, treating the sample by methods well-known to one with ordinary skill in the art, and subjecting said sample to isolation techniques such as chromatography. Chromatography of the sample can be accomplished, for example, by such techniques as high performance liquid chromatography, column chromatography, thin layer chromatography and gas chromatography. The most preferred method of isolation is high performance liquid chromatography.
The stereochemistry of the isolated compound will be dependent upon the metabolic process, and thus may be isolated from the patient as a racemate or a single enantiomer.
The dosage range at which sulfuric acid mono -[3-({1-[2-(4-fluoro-phenyl) ethyl]-piperidin-4-yl}-hydroxy-methyl)-2-methoxy-phenyl]ester and its enantiomers exhibit their ability to block the effects of serotonin at the 5HT2A receptor can vary depending upon the particular disease or condition being treated and its severity, the patient, other underlying disease states the patient is suffering from, and other medications that may be concurrently administered to the patient. Generally though, the compounds will exhibit their serotonin 5HT2A antagonist properties at a dosage range of from about 0.001 mg/kg of patient body weight/day to about 100.0 mg/kg of patient body weight/day. These compounds are typically administered from 1-4 times daily. Alternatively, they can be administered by continuous infusion. The compounds can be administered orally or parenterally to achieve these effects.
The compound of the present invention intended for administration can be formulated into pharmaceutical dosage forms using techniques well known in the art. For oral administration, the compound can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compound can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or algenic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent, which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
For parenteral administration, the compound or its salts may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc. as are known in the art.
The compound may be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the urine, serum, etc. of the patient as is known in the art.
The following examples present typical syntheses as described by Schemes A, B and C and methods for isolation and biological assays. These examples are understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated: xe2x80x9cgxe2x80x9d refers to grams, xe2x80x9cmgxe2x80x9d refers to milligrams xe2x80x9cmmolxe2x80x9d refers to millimoles, mol refers to moles, xe2x80x9cmLxe2x80x9d refers to milliliters, xe2x80x9cxcexcLxe2x80x9d refers to microliters xe2x80x9cxcexcmxe2x80x9d refers to micromoles, xe2x80x9cxcexcMxe2x80x9d refers to micromolar, xe2x80x9cmMxe2x80x9d refers to millimolar xe2x80x9cppmxe2x80x9d refers to parts per million, xe2x80x9cCxe2x80x9d refers to Celsius, xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran, xe2x80x9cMeOHxe2x80x9d refers to methanol, xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate, xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography, xe2x80x9cLCxe2x80x9d or xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography and xe2x80x9cCIMSxe2x80x9d refers to chemical ionization mass spectrum, xe2x80x9cCIDMSxe2x80x9d refers to collision-induced dissociation mass spectrum, xe2x80x9cNMRxe2x80x9d refers to nuclear magnetic resonance, xe2x80x9cIRxe2x80x9d refers to infrared spectroscopy xe2x80x9ctRxe2x80x9d means retention time, xe2x80x9cRfxe2x80x9d means the ratio of the distances which the sample migrates (on TLC) as compared to the distance from the starting point of the solvent front.